PROJECT SUMMARY This proposal is designed to provide a mentored research experience for the applicant that will facilitate the development of an independent research career at the interface of neuroscience, psychiatry, and immunology. For the proposed research, the applicant will build on her preliminary work to determine whether inflammation contributes to comorbid anxiety in major depressive disorder (MDD) though increased amygdala reactivity and decreased amygdala-prefrontal functional connectivity. Comorbid anxiety-related disorders occur in approximately 50% of patients with MDD and are associated with increased morbidity and decreased responsiveness to conventional therapies. Patients with depression, anxiety disorders and post-traumatic stress disorder (PTSD) are also reliably found to exhibit evidence of increased inflammatory activity, which is thought to contribute to the pathophysiology of these highly comorbid illnesses. Relevant in this regard, experimental administration of inflammatory stimuli to humans and laboratory animals has been shown to affect neural activity of the amygdala and functional connectivity of amygdala with other brain regions involved in fear, anxiety and emotional regulation such as the prefrontal cortex (PFC). Despite strong evidence of a role for inflammation in symptoms of both depression and anxiety, no study has examined whether inflammation may contribute to anxiety symptoms in MDD patients. Preliminary results of the applicant collected in patients with MDD who underwent resting-state functional MRI (fMRI) revealed that increased inflammation (as measured by plasma C-reactive protein and inflammatory cytokines) was associated with decreased functional connectivity between the amygdala and ventromedial (vm) PFC. Amygdala-vmPFC connectivity was in turn negatively correlated with symptoms of anxiety (as derived from the Hamilton Depression Rating Scale) and this relationship was seen only in patients with a comorbid anxiety disorder and/or PTSD. Given this foundation, we hypothesize that inflammation affects amygdala reactivity to disrupt amygdala-vmPFC circuitry, which in turn drives transdiagnostic symptoms of anxiety in patients with MDD. To test this central hypothesis, MDD patients (~50% with comorbid anxiety disorders and/or PTSD) and a range of inflammation levels will undergo 1) fMRI to examine relationships between inflammation and amygdala reactivity (neural activation to fearful faces) and amygdala-vmPFC functional connectivity, and 2) clinician-administered and self-report scales of anxiety and PTSD symptom severity to further solidify relationships between inflammation, amygdala- vmPFC circuitry and symptoms of anxiety and hyperarousal. Elucidating the role of inflammation in comorbid anxiety-related disorders in MDD may lead to development of new therapeutic targets to personalize treatment for these patients. To accomplish her research and career development goals, the applicant?s training will include a combination of mentored research from a team with expertise in neuroimaging, immunology and psychiatry, as well as coursework, seminars, and attendance at national and international meetings.